Phase I Evaluation of Crisnatol (BWA770U Mesylate) on a Monthly Extended Infusion Schedule

PURPOSE This phase I study was performed to assess the feasibility of the combination of docetaxel and cisplatin and to determine the maximum-tolerated dose (MTD) and the side effects with an emphasis on sequence-dependent side effects. MATERIALS AND METHODS Patients who were not pretreated with taxanes or cisplatin derivatives and who had received no more than one prior combination chemotherapy regimen or two single-agent regimens were entered. Treatment consisted of docetaxel given as a 1-hour infusion followed by cisplatin as a 3-hour infusion (schedule A), or cisplatin followed by docetaxel (schedule B). Docetaxel doses ranged from 55 to 100 mg/m2 and cisplatin doses from 50 to 100 mg/m2. RESULTS Leukocytopenia and granulocytopenia were common (overall, 90%; grade 3 or 4, 87%), short-lasting, and docetaxel dose-dependent. Infections and neutropenic fever occurred in 10% and 4.5% of courses, respectively. Nonhematologic toxicities were mild to moderate and included alopecia, nausea, vomiting, diarrhea, mucositis, neurotoxicity, fluid retention, and skin and nail toxicity. There were no significant differences in pharmacokinetic parameters between schedules A and B. Tumor responses included one complete response (CR) and nine partial responses (PRs). CONCLUSION The dose levels docetaxel 100 mg/m2 plus cisplatin 75 mg/m2 and docetaxel 85 mg/m2 plus cisplatin 100 mg/m2 appeared to be manageable. At these dose levels, the median relative dose-intensity was high and 81% and 88% of all cycles, respectively, could be given at full dose. Schedule A is advocated for further treatment.

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A phase I trial of aprinocarsen (ISIS 3521/LY900003), an antisense inhibitor of protein kinase C-α administered as a 24-hour weekly infusion schedule in patients with advanced cancer

Investigational New Drugs ◽

10.1007/s10637-005-2906-0 ◽

2005 ◽

Vol 23 (5) ◽

pp. 467-477 ◽

Cited By ~ 26

Author(s):

Ranjana Advani ◽

Bert L. Lum ◽

George A. Fisher ◽

Joanne Halsey ◽

Richard S. Geary ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Phase I ◽

Advanced Cancer ◽

Phase I Trial ◽

Weekly Infusion ◽

Kinase C ◽

Infusion Schedule

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Phase I Clinical Investigation of Fludarabine Phosphate by a Loading-Dose and Continuous-Infusion Schedule

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/80.6.447 ◽

1988 ◽

Vol 80 (6) ◽

pp. 447-449 ◽

Cited By ~ 14

Author(s):

J. M. Leiby ◽

M. R. Grever ◽

A. E. Staubus ◽

J. A. Neidhart ◽

L. Malspeis

Keyword(s):

Phase I ◽

Continuous Infusion ◽

Clinical Investigation ◽

Loading Dose ◽

Fludarabine Phosphate ◽

Infusion Schedule

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A phase I and pharmacodynamic study of a 7 day infusion schedule of the DNMT1 antisense compound MG98

Journal of Clinical Oncology ◽

10.1200/jco.2005.23.16_suppl.3070 ◽

2005 ◽

Vol 23 (16_suppl) ◽

pp. 3070-3070 ◽

Cited By ~ 3

Author(s):

L. Vidal ◽

M. Leslie ◽

J. Sludden ◽

M. G. Griffin ◽

R. Plummer ◽

...

Keyword(s):

Phase I ◽

Pharmacodynamic Study ◽

Infusion Schedule

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Constant infusion schedule for adriamycin: a phase I-II clinical trial of a 30-day schedule by ambulatory pump delivery system.

Journal of Clinical Oncology ◽

10.1200/jco.1983.1.1.24 ◽

1983 ◽

Vol 1 (1) ◽

pp. 24-28 ◽

Cited By ~ 55

Author(s):

J Lokich ◽

A Bothe ◽

T Zipoli ◽

R Green ◽

H Sonneborn ◽

...

Keyword(s):

Phase I ◽

Continuous Infusion ◽

Dose Rate ◽

Infusion Pump ◽

Substantial Reduction ◽

Drug Effects ◽

Phase Iii ◽

Constant Infusion ◽

Clinical Activity ◽

Infusion Schedule

Eighteen patients received a continuous intravenous infusion of adriamycin for 14-60 days in a phase I study in which the dose rates were escalated from 2 mg/sq m/day to 5 mg/sq m/day to establish the optimal dose to be delivered over a 30-day period. The drug was delivered via a tunneled subclavian catheter by a portable infusion pump (Cormed model ML-6) primed to provide a volume of diluted drug of 10 cc/day. Leukopenia and stomatitis were observed at 4 mg/sq m/day doses or greater in 50% of courses. At doses less than 4 mg/sq m/day, only 3/17 courses (18%) were associated with stomatitis. Partial alopecia developed in all patients, but less than 50% of scalp hair was affected. The cumulative dose of continuous infusion adriamycin at 30 days is comparable to the dose delivered by standard bolus intermittent schedules (60-90 mg/sq m g 21 days), but the adverse drug effects are eliminated or substantially reduced. Cardiac toxicity was assessed in selected patients treated to 450 mg/sq m or greater by cardiac biopsy and/or gated pool studies. No histopathologic lesions were noted in 3 patients receiving 450 mg/sq m or greater. The recommended daily dose rate of adriamycin in this protracted infusion regimen is 3 mg/sq m/day. The phase II study of this schedule and dose rate in 38 additional patients (a total of 52 evaluable patients) demonstrated objective responses in 1/9 soft tissue sarcoma, 1/3 mesothelioma, 1/3 hepatoma, and 2/13 breast cancer. Phase III studies of the protracted continuous infusion schedule for adriamycin are indicated in that clinical activity is demonstrated at a substantial reduction in toxicity. Pharmacologic studies expanding the existing data base are also necessary.

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Phase I clinical trial of taxotere administered as either a 2-hour or 6-hour intravenous infusion.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.5.950 ◽

1993 ◽

Vol 11 (5) ◽

pp. 950-958 ◽

Cited By ~ 88

Author(s):

H Burris ◽

R Irvin ◽

J Kuhn ◽

S Kalter ◽

L Smith ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trial ◽

Phase I ◽

Phase Ii ◽

Antineoplastic Agent ◽

Plasma Concentrations ◽

Phase I Clinical Trial ◽

Pharmacokinetic Studies ◽

Infusion Schedule ◽

Dose Limiting Toxicity

PURPOSE To determine the potential efficacy and dose-limiting toxicity of taxotere, a hemisynthetic inhibitor of tubulin depolymerization. PATIENTS AND METHODS Fifty-eight patients were administered taxotere in this phase I clinical trial as a 6-hour or a 2-hour infusion repeated every 21 days. Forty patients received 181 courses on the 6-hour infusion schedule, and 18 patients received 105 courses on the 2-hour infusion schedule. RESULTS Neutropenia was the dose-limiting toxicity on both schedules. The maximally tolerated dose was 100 mg/m2 on the 6-hour infusion schedule and 115 mg/m2 on the 2-hour infusion schedule. The most prominent nonhematologic toxicities included mucositis (more prominent on the 6-hour infusion schedule), transient rash (more common on the 2-hour infusion schedule), and alopecia. Hypersensitivity reactions were seen in five patients. There was no evidence of neurotoxicity or cardiotoxicity. One partial response was noted on the 6-hour infusion schedule (one in refractory breast cancer) and four additional partial responses were noted on the 2-hour infusion schedule (two in adenocarcinoma of the lung, one in refractory breast cancer, one in cholangio-carcinoma). In addition, 10 patients had minor responses. Pharmacokinetic studies showed plasma concentrations of taxotere declined in a triexponential manner, with a terminal half-life of 11.8 hours. CONCLUSION The recommended starting dose for phase II taxotere trials is 100 mg/m2 administered as a 2-hour infusion, repeated every 21 days. Taxotere is a promising antineoplastic agent worthy of extensive phase II testing in patients with a variety of malignancies.

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